Abstract
Introduction Pulmonary alveolar proteinosis related to mutations in the methionine tRNA synthetase (MARS1) gene is a severe, early-onset disease that results in death before the age of 2 years in one-third of patients. It is associated with a liver disease, growth failure and systemic inflammation. As methionine supplementation in yeast models restored normal enzymatic activity of the synthetase, we studied the tolerance, safety and efficacy of daily oral methionine supplementation in patients with severe and early disease.
Methods Four patients received methionine supplementation and were followed for respiratory, hepatic, growth and inflammation-related outcomes. Their course was compared to those of historical controls. Reactive oxygen species production by patient monocytes before and after methionine supplementation was also studied.
Results Methionine supplementation was associated with respiratory improvement, clearance of the extracellular lipoproteinaceous material and discontinuation of whole-lung lavage in all patients. The three patients who required oxygen or noninvasive ventilation could be weaned off within 60 days. In addition, liver dysfunction, inflammation and growth delay improved or resolved. At a cellular level, methionine supplementation normalised the production of reactive oxygen species by peripheral monocytes.
Conclusion Methionine supplementation was associated with important improvements in children with pulmonary alveolar proteinosis related to mutations in the MARS1 gene. This study paves the way for similar strategies for other tRNA synthetase deficiencies.
Abstract
Pulmonary alveolar proteinosis related to mutations in MARS1 is a rare and severe lung disease with early onset and no curative treatment to date. In four affected children we showed that methionine supplementation is an effective treatment. https://bit.ly/2WlbcOz
Footnotes
This article has an editorial commentary: https://doi.org/10.1183/13993003.02971-2021
Author contributions: A. Hadchouel, D. Drummond, C. Pontoizeau, M-M. Hurtado-Nedelec, J. El Benna, M. Schiff, T.J. Molina, L. Berteloot, C. Ottolenghi, J-M. Tréluyer, J. de Blic and C. Delacourt contributed to the conception and design of the study, the acquisition, analysis and interpretation of data for the study. L. Aoust, E. Gachelin, C. Perisson, C. Vigier, F. Lacaille and S. Renolleau contributed to the acquisition of the data for the study and revised the draft of the manuscript. A. Hadchouel, D. Drummond and C. Delacourt drafted the work and revised it after revision by the other authors. All authors approved the final version to be published.
Conflict of interest: A. Hadchouel reports grants from APHP and Fonds de Recherche en Santé Respiratoire–Fondation du Souffle, during the conduct of the study; and has a patent EP 21 305 689.8 pending.
Conflict of interest: The remaining authors have nothing to disclose.
Support statement: This work was funded by La Fondation du Souffle et le Fonds de Recherche en Santé Respiratoire (SRC2017) and La Cellule Recherche et Innovation de l'APHP, Hôpital Necker. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received June 2, 2021.
- Accepted August 17, 2021.
- Copyright ©The authors 2022. For reproduction rights and permissions contact permissions{at}ersnet.org